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Meta-Analysis
. 2016 Jun 6;2016(6):CD008334.
doi: 10.1002/14651858.CD008334.pub2.

Biologic interventions for fatigue in rheumatoid arthritis

Celia Almeida  1 , Ernest H S Choy, Sarah Hewlett, John R Kirwan, Fiona Cramp, Trudie Chalder, Jon Pollock, Robin Christensen
Affiliations
Meta-Analysis

Biologic interventions for fatigue in rheumatoid arthritis

Celia Almeida et al. Cochrane Database Syst Rev. .

Abstract

Background: Fatigue is a common and potentially distressing symptom for patients with rheumatoid arthritis (RA), with no accepted evidence-based management guidelines. Evidence suggests that biologic interventions improve symptoms and signs in RA as well as reducing joint damage.

Objectives: To evaluate the effect of biologic interventions on fatigue in rheumatoid arthritis.

Search methods: We searched the following electronic databases up to 1 April 2014: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Current Controlled Trials Register, the National Research Register Archive, The UKCRN Portfolio Database, AMED, CINAHL, PsycINFO, Social Science Citation Index, Web of Science, and Dissertation Abstracts International. In addition, we checked the reference lists of articles identified for inclusion for additional studies and contacted key authors.

Selection criteria: We included randomised controlled trials if they evaluated a biologic intervention in people with rheumatoid arthritis and had self reported fatigue as an outcome measure.

Data collection and analysis: Two reviewers selected relevant trials, assessed methodological quality and extracted data. Where appropriate, we pooled data in meta-analyses using a random-effects model.

Main results: We identified 32 studies for inclusion in this current review. Twenty studies evaluated five anti-tumour necrosis factor (anti-TNF) biologic agents (adalimumab, certolizumab, etanercept, golimumab and infliximab), and 12 studies focused on five non-anti-TNF biologic agents (abatacept, canakinumab, rituximab, tocilizumab and an anti-interferon gamma monoclonal antibody). All but two of the studies were double-blind randomised placebo-controlled trials. In some trials, patients could receive concomitant disease-modifying anti-rheumatic drugs (DMARDs). These studies added either biologics or placebo to DMARDs. Investigators did not change the dose of the latter from baseline. In total, these studies included 9946 participants in the intervention groups and 4682 participants in the control groups. Overall, quality of randomised controlled trials was moderate with a low to unclear risk of bias in the reporting of the outcome of fatigue. We downgraded the quality of the studies from high to moderate because of potential reporting bias (studies included post hoc analyses favouring reporting of positive result and did not always include all randomised individuals). Some studies recruited only participants with early disease. The studies used five different instruments to assess fatigue in these studies: the Functional Assessment of Chronic Illness Therapy Fatigue Domain (FACIT-F), Short Form-36 Vitality Domain (SF-36 VT), Visual Analogue Scale (VAS) (0 to 100 or 0 to 10) and the Numerical Rating Scale (NRS). We calculated standard mean differences for pooled data in meta-analyses. Overall treatment by biologic agents led to statistically significant reduction in fatigue with a standardised mean difference of -0.43 (95% confidence interval (CI) -0.38 to -0.49). This equates to a difference of 6.45 units (95% CI 5.7 to 7.35) of FACIT-F score (range 0 to 52). Both types of biologic agents achieved a similar level of improvement: for anti-TNF agents, this stood at -0.42 (95% CI -0.35 to -0.49), equivalent to 6.3 units (95% CI 5.3 to 7.4) on the FACIT-F score; and for non-anti-TNF agents, it was -0.46 (95% CI -0.39 to -0.53), equivalent to 6.9 units (95% CI 5.85 to 7.95) on the FACIT-F score. In most studies, the double-blind period was 24 weeks or less. No study assessed long-term changes in fatigue.

Authors' conclusions: Treatment with biologic interventions in patients with active RA can lead to a small to moderate improvement in fatigue. The magnitude of improvement is similar for anti-TNF and non-anti-TNF biologics. However, it is unclear whether the improvement results from a direct action of the biologics on fatigue or indirectly through reduction in inflammation, disease activity or some other mechanism.

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Conflict of interest statement

At the time of protocol development Sarah Hewlett was in receipt of a small unrestricted educational grant from GlaxoSmithKline to partially fund a PhD studentship on fatigue measurement in RA and also undertaking an RCT of cognitive behavioural therapy (CBT) for the self‐management of RA fatigue, funded by the Arthritis Research Campaign. During the full review process Sarah Hewlett has been undertaking an RCT of CBT for the self‐management of RA fatigue by the clinical team, funded by the National Institutes for Health Research. She has received small consultancy fees from UCB Pharmaceuticals and Bristol Myers Squibb to advise on the translation of the Bristol RA Fatigue Scales, and small, unrestricted educational grants from Pfizer to deliver training days for staff, in which non‐pharmacological management of fatigue was included. These associations reflect our large programme of research in fatigue into RA but do not constitute a conflict of interests. Robin Christensen has received consulting fees paid to the Parker Institute from Abbott/AbbVie, Axellus A/S, Bristol‐Myers Squibb, Cambridge Weight Plan, Norpharma, Pfizer and Roche; speakers fees paid to the Parker Institute from Axellus A/S, Cambridge Weight Plan, Mundipharma, Roche, and Rottapharm‐MEDA; research grants paid to the Parker Institute from Abbott/AbbVie, Axellus, Bayer HealthCare Pharmaceuticals, Biogen Idec, Bristol‐Myers Squibb, Cambridge Weight Plan, Ipsen, Laboratoires Expanscience, MSD, Mundipharma/Norpharma, Pfizer, and Roche. John Kirwan has been a paid adviser to the Royal Pharmaceutical Society and British Medical Association publication the British National Formulary during the time of this review. He also had unconditional educational grants from Horizon Pharma for the cost of attending the American College of Rheumatology Annual Scientific Meeting in 2013 and the cost of travel to the American College of Rheumatology Annual Scientific Meeting in 2014. Ernest Choy and Cardiff University has received research grants from Ferring Pharmaceuticals, Novimmune, Pfizer, Roche, and UCB. Ernest Choy has received payment as member of advisory boards and lecture fees from Amgen, Biogen, BMS, Celgene, Chugai Pharma, Eli Lilly, Ferring Pharmacuetical, Hospita, Jenssen, MSD, Napp, Novimmune, Pfizer, Regeneron, Roche, Sanofi, Tonix and UCB. Trudie Chalder is author of self help books for chronic fatigue and receives some royalties. Celia Almeida, Fiona Camp and Jon Pollock have no conflict of interest to declare.

Figures

1
1
Study flow diagram
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Funnel plot of comparison: 1 All Biologics, outcome: 1.1 All studies ‐ fatigue continuous measures.
4
4
Forest plot of comparison: 1 All Biologics, outcome: 1.1 All studies ‐ fatigue continuous measures.
5
5
Forest plot of comparison: 4 Subgroup comparison: anti‐TNF vs non anti‐TNF, outcome: 4.1 Anti‐TNF and non anti‐TNF ‐ fatigue continuous measures.
1.1
1.1. Analysis
Comparison 1 All biologics, Outcome 1 All studies ‐ fatigue continuous measures.
2.1
2.1. Analysis
Comparison 2 Subgroup comparison : anti‐TNF vs non‐anti‐TNF , Outcome 1 Anti‐TNF and non anti‐TNF ‐ fatigue continuous measures.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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Genovese 2008 {published data only}
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Keystone 2009 {published and unpublished data}
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Kremer 2003 {published data only}
    1. Emery P, Kosinski M, Li T, Martin M, Williams GR, Becker JC, et al. Treatment of rheumatoid arthritis patients with abatacept and methotrexate significantly improved health‐related quality of life. Journal of Rheumatology 2006;33(4):681‐9. - PubMed
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Kremer 2006 {published data only}
    1. Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud‐Mendoza C, et al. Effects of abatacept in patients with methotrexate‐resistant active rheumatoid arthritis: a randomized trial. Annals of Internal Medicine 2006;144(12):865‐76. - PubMed
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Li 2013 {published data only (unpublished sought but not used)}
    1. Li Z, Zhang F, Kay J, Fei K, Han C, Zhuang Y, Wu Z. Safety and efficacy of subcutaneous golimumab In Chinese patients with active rheumatoid arthritis despite MTX therapy: results from a randomized, placebo‐controlled, phase 3 trial. Arthritis and Rheumatology 2013;65(Suppl 10):1416. [DOI: 10.1002/art.2013.65.issue-s10] - DOI - PubMed
Lukina 1998 {published data only}
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Maini 1999 {published data only}
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Mittendorf 2007 {published data only}
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Moreland 1999 {published data only}
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Pope 2012 {published data only}
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Rigby 2011 {published data only}
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Schiff 2008 {published data only}
    1. Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi‐centre, randomised, double‐blind, placebo‐controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Annals of the Rheumatic Diseases 2008;67(8):1096‐103. - PMC - PubMed
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Smolen 2008 {published data only}
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Smolen 2009a {published data only}
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Smolen 2009b {published data only}
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Soubrier 2009 {published data only}
    1. Soubrier M, Puéchal X, Sibilia J, Mariette X, Meyer O, Combe B, et al. Evaluation of two strategies (initial methotrexate monotherapy vs its combination with adalimumab) in management of early active rheumatoid arthritis: data from the GUEPARD trial. Rheumatology 2009;48(11):1429‐34. - PubMed
Strand 2009 {published data only}
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Strand 2012a {published data only}
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Strand 2012b {published data only}
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Weinblatt 2003 {published data only}
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Weinblatt 2013 {published data only}
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References to studies excluded from this review

Breedveld 2005 {published data only}
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Gnanasakthy 2013 {published data only}
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Grigor 2004 {published data only}
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Kremer 2008 {published data only}
    1. Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud‐Mendoza C, et al. Results of a two‐year follow‐up study of patients with rheumatoid arthritis who received a combination of abatacept and methotrexate. Arthritis and Rheumatism 2008;58(4):953‐63. - PubMed
Moreland 2000 {published data only}
    1. Moreland LW, McCabe DP, Caldwell JR, Sack M, Weisman M, Henry G, et al. Phase I/II trial of recombinant methionyl human tumor necrosis factor binding protein PEGylated dimer in patients with active refractory rheumatoid arthritis. Journal of Rheumatology 2000;27(3):601‐9. - PubMed
Moreland 2002 {published data only}
    1. Moreland LW, Alten R, Bosch F, Appelboom T, Leon M, Emery P, et al. Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose‐finding, double‐blind, placebo‐controlled clinical trial evaluating CTLA‐4Ig and LEA29Y eighty‐five days after the first infusion. Arthritis and Rheumatism 2002;46(6):1470‐9. - PubMed
Sansonno 2003 {published data only}
    1. Sansonno D, Re V, Lauletta G, Tucci FA, Boiocchi M, Dammacco F. Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti‐CD20. Blood 2003;101(10):3818‐26. - PubMed
Song 2007 {published data only}
    1. Song YW, Lee EY, Koh EM, Cha HS, Yoo B, Lee CK, et al. Assessment of comparative pain relief and tolerability of SKI306X compared with celecoxib in patients with rheumatoid arthritis: a 6‐week, multicenter, randomized, double‐blind, double‐dummy, phase III, noninferiority clinical trial. Clinical Therapeutics 2007;29(5):862‐73. - PubMed
Strand 2012 {published data only}
    1. Strand V, Jones TV, Li W, Koenig AS, Kotak S. Factors that impact work productivity in the preserve trial: A randomized controlled trial of combination etanercept‐methotrexate therapy in patients with moderately active rheumatoid arthritis. Arthritis and Rheumatism 2012;64(S10):S777.
Strand 2014 {published data only}
    1. Strand V, Kosinski M, Gnanasakthy A, Mallya U, Mpofu S. Secukinumab treatment in rheumatoid arthritis is associated with incremental benefit in the clinical outcomes and HRQoL improvements that exceed minimally important thresholds. Health and Quality of Life Outcomes 2014;12(1):31‐40. - PMC - PubMed
Tak 2008 {published data only}
    1. Tak PP, Thurlings RM, Rossier C, Nestorov I, Dimic A, Mircetic V, et al. Atacicept in patients with rheumatoid arthritis: Results of a multicenter, phase Ib, double‐blind, placebo‐controlled, dose‐escalating, single‐ and repeated‐dose study. Arthritis and Rheumatism 2008;58(1):61‐72. - PubMed
Yount 2007 {published data only}
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References to ongoing studies

St Clair 2004 {published data only}
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Van der Kooij 2009 {published data only}
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Westhovens 2006 {published data only}
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Additional references

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